FI78682C - FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT ANVAENDBARA OXIMETRAR. - Google Patents

Description

78682

The present invention relates to a process for the preparation of new therapeutically useful oxime ethers of the E, E configuration. In particular, the present invention relates to a process for the preparation of basic oxime ethers having an anesthetic-enhancing, antianginal, analgesic and / or antiarrhythmic effect.

H (J Patent 169,298 discloses basic oxime ethers having local anesthetic, antispasmodic, antiparkinsonian, antiepileptic and antidepressant activity. According to this patent, said compounds can be prepared by reacting the corresponding ketone or thione with aminoalkyl hydroxyl derivatives or reacting the corresponding oxime with a haloalkylamine derivative and amination of the halogen derivative thus obtained.

According to the present invention, it has been found that certain novel basic oxime ethers, which fall within the scope of the general formula of HU patent 169,298, but which are not actually disclosed therein, have a spectrum of activity which differs considerably from that of the compounds disclosed in said Hungarian patent. The novel compounds of the present invention have a significant anesthetic enhancing and analgesic effect in addition to the beneficial antiarrhythmic effect, and at the same time the antagonistic effect of reserpine characteristic of the antidepressant effect is virtually eliminated. HU patent publication 169,298 does not disclose the anesthetic, analgesic or antiarrhythmic effect of the compounds.

2,78682

According to the present invention, there is provided a general formula / CH 2 CH-HC (CH 3) 2 I 2 | / C HC (CH3) 2

CH

R

and their pharmaceutically acceptable acid addition salts according to the formula wherein R is phenyl or 4-chlorophenyl.

The compound of general formula (I) has the Ε, Ε configuration.

The acid addition salts of the compounds of general formula (I) may be addition salts formed with pharmaceutically acceptable inorganic or organic acids, e.g. hydrochlorides, hydrobromides, sulphates, phosphates, acetates, propionates, methanesulphonates, p-toluenesulphonates, tartrates, sulphonates, , fumarates, citrates, malates, lactates, etc.

The present invention therefore relates to a process for the preparation of therapeutically useful compounds of general formula (I) having the E, E configuration, wherein R represents phenyl or 4-chlorophenyl, and to pharmaceutically acceptable acid addition salts of these compounds, which process comprises a) II) CH, 3 78682 f »2 = ¾ CH, C * X (II)

II

CH

R

A compound having the Ε, konf configuration according to the formula is reacted with a compound of the general formula (III) HC (CH 2), / 3 2 Y- (CH 2) 3 -N 2 (III) hc (ch 3) 2 or an acid addition salt thereof, wherein X represents a hydroxyimino group of formula * N-OH and Y represents halogen and R represents the same as above, or b) reacting a compound of general formula (II) with an E, E configuration with Y- (CH2) 3 of general formula (IV) ~ Hal1 (IV) and treated with the general formula (V) .CH, <^ 2 f 2 CH, C = N-O- (CH) -Hai1 (v) ν '

II

CH

R

a compound having the Ε, konf configuration according to the formula (VI) 4 78682 HC (CH 2) 0/3 2 HN 2 (VI) hc (ch 3) 2 or an acid addition salt thereof, wherein Y, X and R have the same meanings as defined above and Hal 'is halogen, and if desired, the compound of general formula (I) obtained by method a) or b) is converted into a pharmaceutically acceptable acid addition salt or the base is liberated from the salt.

The term "halogen" means fluorine, chlorine, bromine or iodine atoms.

According to process a) of the present invention, a compound of general formula (II) in which X represents a hydroxyimino group of formula = NOH is reacted with a compound of general formula (III) in which Y is halogen. This reaction can be conveniently carried out in the presence of a basic condensing agent. Alkali amides (e.g. sodium or potassium amide), alkali metal hydrides (e.g. sodium or potassium hydride), alkali metal alcoholates (e.g. sodium methylate, sodium ethylate or potassium tert-butylate) or alkali hydroxides (e.g. sodium or potassium hydroxide) can be used for this purpose. ). The reaction can be carried out in an inert organic solvent. The reaction medium depends on the basic condensing medium used. If alkamides or alkali metal hydrides are used, the reaction may be carried out in an aromatic hydrocarbon (e.g. benzene or toluene). If an alkali metal alcoholate is used as the basic condensing agent, the alcohol corresponding to the alcoholate can advantageously act as a reaction medium. If alkali hydroxides are used as the basic condensing agent, the reaction can be preferably carried out in an aqueous medium. The haloalkylamine of the general formula 5 78682 (III) can also be used in the form of an acid addition salt, in particular as the hydrochloride. The reaction can be carried out at a temperature between 20 ° C and the boiling point of the reaction mixture, suitably at 30 to 60 ° C.

In the first step of process b), a compound of general formula (II) is reacted with a halogen derivative of general formula (IV). The reaction may conveniently be carried out in the presence of a basic condensing agent. For this purpose, for example, alkali amides (e.g. sodium or potassium amide), alkali metal hydrides (e.g. sodium or potassium hydride) or time metals can be used. The reaction may conveniently be carried out in an inert organic solvent. The reaction medium depends on the basic condensing medium used. If alkali amides or alkali metal hydrides are used as the basic condensing agent, preferably aromatic hydrocarbons (e.g. benzene, toluene, xylene or cumene) can act as a reaction medium. If an alkali metal is used as the basic condensing agent, the reaction may conveniently be carried out in a lower aliphatic alcohol (e.g. methanol or ethanol, etc.).

The compound of general formula (V) formed in the second step of process B) is reacted with an amine of general formula (VI) or an acid addition salt thereof. The amination is preferably performed under pressure in an autoclave.

The isolation and purification of the compounds of general formula (I) can be carried out by methods known per se.

The compounds of general formula (I) can be converted into their acid addition salts by methods known per se. The salt formation can be preferably carried out in an inert organic solvent.

The starting materials used in the process of the present invention are known or can be prepared according to the methods disclosed in HU Patent Publication No. 169,298.

The compounds of general formula (I) have valuable anesthetic, antianginal analgesic and antiarrhythmic properties. The pharmacological activity of the novel compounds of the present invention is demonstrated by the following standard tests.

1) Acute toxicity in mice

Acute toxicity is determined in male and female white CFLP mice. The animals weigh 18 to 24 g. The test compound is administered orally in a dose of 20 ml per kg. After treatment, the animals are placed in a mouse box and kept on the chew at room temperature. The animals receive mouse feed and tap water to their liking. After treatment, the animals are observed for 4 days and the toxicity values are determined graphically.

2) Analgesic effect in mice

Mice are given 0.4 ml of 0.5% acetic acid intravenously. After 5 minutes, characteristic torsional response reactions are counted over 5 minutes. The test compound is administered orally one hour before the administration of acetic acid. Activity is expressed as a percentage of the values obtained for the control group. The results are shown in Table I.

Table I

7 78682

Analgesic effect in mice

Test compound LD50mg / kg EDsomg / kg Therapeutic index

Example No. 1 1100 45 24.2

Paracetamol 510 180 2.8

Reference compound F 1750 is inactive at a dose of 350 mg / kg

Reference compound A 250 is inactive at a dose of 50 mg / kg

Reference compound G 325 is inactive at a dose of 65 mg / kg

The table shows that the analgesic effect of the new compounds of general formula (I) is many times stronger than that of paracetamol on the market. On the other hand, the known compounds, which are specifically disclosed in HU patent publication 169,298, do not have analgesic properties. 1

Antiarrhythmic effect in rats The antiarrhythmic effect is determined in rats (both male and female, weight 160-200 g) according to a variation of the test described in [Marmo et al .: Arzneimittelforschung (drug Research) 2 £, 12 (1970)]. Aconitine is administered intravenously in the form of a bolus injection. ECG abnormalities are monitored for 5 minutes by the standard II method. The test compound is administered intravenously 2 minutes before aconitine administration. The test results are shown in Table II.

β 78682

Table II

Antiarrhythmic effect in rats

Test compound Dose mg / kg iv. Percent inhibition of aconitine 3 1 86.2

Lidocaine 4 23.5

The values in Table II show that the novel compounds of the present invention have a stronger antiarrhythmic effect than lidocaine. This effect occurs with both intravenous and oral administration.

Table 10 compares the antiarrhythmic effect of the compound of the present invention with that of the highly active compound disclosed in HU Patent Publication No. 169,298. The test is performed as shown in Table II.

Table III

Antiarrhythmic effect in mice

Test Compound LDsomg / kg Percent Therapeutic i.v. effect in mice index

Example 2 12.50 0.54 23.14

Reference compound G 21.19 2.00 10.59

The above values indicate that the novel compound of the present invention is superior to the known derivative in terms of both absolute dose and therapeutic index.

, 78682 4) Antianginal effect in rats The experiments were performed on male rats weighing 180-220 g. Animals were anesthetized using chloro-ales-urethane (70/700 mg / kg i.p.). The ECG was recorded using needle electrodes with a standard II measurement. The antianginal effect was tested according to the method of Nieschuls (Arch. Int. Pharmacodyn, 160, 147, (1966)). Experimental coronary insufficiency was induced by glandu-itrin injection (4 IU / kg i.v.) in which 10 to 12 animals were treated with each dose. The results are shown in Tables IV and V.

Table iv

Test Compound Dose Inhibition mg / kg% i.v.

Example No. 1 0.5 72.0 2 0.5 57.0

Premylamine 2.0 32.0

Reference compound G 3.0 Ineffective (slightly worsened) - "- 4.0 —n—

Table V

io 78682

Effect of antiarrhythmics on oral administration in rats

Test compound Dose Inhibition mg / kg% 2 50 55.2

Reference compound G 60 4.6

Lidocaine 60 0

It can be seen from Table V that the compound of Example 2 has a significant inhibitory effect even when administered orally, while the known compound G and lidocaine are ineffective at the respective doses.

The above results prove that the compounds of the invention have an excellent antianginal effect which is several times higher than prenylamine.

Reference compound G has no antianginal effect in the amounts used, it even exacerbates the experimentally induced coronary insufficiency.

The following reference compounds are used in the above tests:

Meprobamate = 2-methyl-2-n-propyl-1,3-propanediol dicarbamate;

Paracetamol = 4-hydroxyacetanilide;

Lidocaine = N, N-diethyl-2,6-dimethylacetanilide; Reference Compound A = 2-benzyl-1- (3'-dimethylamino-propoxyimino) -cyclohexane (HU Patent Publication 169,298, Example 34); Reference Compound B * 1-12 * -methyl-3 '- (4' '- methyl-piperazinyl) -propoxyimino] -2- (p-methoxy-78682 benzyl) -cyclohexane (HU Patent Publication 169,298 , Example 26);

Reference Compound C = 1- (2'-methyl-3'-dimethylamino-propoxyimino) -2- (o-methoxy-benzal) -cyclohexane (HU Patent 169,298, Example 21);

Reference Compound D = 2- (p-chloro-benzyl) -1- [3 '- (4' '- methyl-piperazinyl) -propoxyimino] -cyclohexane (Ηϋ-Patent 169,298, Example 44);

Reference Compound E * 1- (3'-Dimethylamino-propoxyimino) -2- (p-chlorobenzyl) -cyclohexane (HU Patent Publication 169,298, Example 45); Reference compound F * 1- (3'-dimethylcunino-propoxyimino) -2- (p-methoxybenzal) -cyclohexane (HU Patent Publication 169,298, Example 41); Reference compound G * 2-benzal-1- (2'-diisopropylaminoethoxyimino) -cycloheptane (HU Patent Publication 169,298, Example 14).

Further details of the present invention are set forth in the examples without limiting the scope of the protection to the examples.

Example 1 Preparation of 2 - [(E) - (p-chlorophenylmethylene)] - [- (E) - (31-diisopropylamino-propoxyimino)] - cyclohexane

To the apparatus fitted with a stirrer add 50 ml of water, 40 g of sodium hydroxide and 10 g of potassium hydroxide. After complete dissolution, a solution of 23.57 g (0.1 mol) of 2-t (E) - (p-chlorophenylmethylene)] - cyclohexanin-1-one (E) -oxime in 30 ml of dimethyl sulfoxide is added. and 15.65 g (0.1 mol) of 1-bromo-3-chloropropane at 50-60 ° C. The reaction mixture is allowed to stand at this temperature for a few hours. The upper oily layer is separated (weight: 12,78682 26.5 g), 100 ml of dimethylformamide and 20.2 g (0.2 mol) of N, N-diisopropylamine are added. The mixture is stirred at 100 [deg.] C. for 5 hours, poured into 200 g of ice-cold water, extracted with benzene, the benzene layer is washed neutral and evaporated. 32.05 g of the desired compound are thus obtained in the form of a pale yellow oil, yield 85%.

2- (E) -butenedioate (1/1) melts at 87-89.5 ° C.

Analysis for C 26 H 37 ClN 2 O 5 (493.06): Calculated: C% = 63.34, H% = 7.56, Cl% = 7.19, N% 5.68; found: C% 63.28, H% * 7.73, Cl% * 6.95, N% * 5.43.

U.V .: Jlmax = 280 nm (E - 17456) The melting point of the 2- (E) -butenedioate / water (1/1/1) salt is 117-119 ° C.

Analysis for C 26 H 39 ClN 2 O 6 (511.05): Calculated: C% = 61.10, H% * 7.69, Cl% = 6.94, N% 5.48; found: C% * 61.15, H% * 7.73, Cl% * 6.95, N% = 5.43.

Example 2 Preparation of 2 - [(E) -phenylmethylene] -1 - [(E) - (3'-diisopropylamino-propoxyimino)] - cyclohexane

The procedure is as in Example 1, but using 20.13 g (0.1 mol) of 2- (E) -phenylmethylene-cyclohexan-1-one (E) -oxime as starting material. Thus 28.47 g of the desired compound are obtained, yield 83.1%. The 2- (E) -butenedioate (1/1) salt melts at 129-131 ° C.

Analysis for C 26 H 38 N 2 O 5 (458.61): Calculated: C% = * 68.09, H% = 8.35, N% = 6.10; found: C, 67.94; H, 8.47; N, 6.15.

U.V. J * max * 275 nm (& = 14196) i3 7 8 6 8 2

Example 3 Preparation of 2 - [(E) -phenylmethylene] -1 - [(E) - (31-diisopropylamino-propoxyimino)] - cyclohexane

To the apparatus fitted with a stirrer add 50 ml of water, 40 g of sodium hydroxide and 10 g of potassium hydroxide. After complete dissolution, a solution of 20.13 g (0.1 mol) of 2- (E) -phenylmethylenecyclohexan-1-one- (E) -oxime in 30 ml of dimethyl sulfoxide is added, followed by 23.55 g (0 mol) of , 11 moles) of 1-diisopropylamino-3-chloropropane hydrochloride in several portions. During the addition, the temperature rises to 50-55 ° C. The reaction mixture is subjected to a post-reaction at room temperature for several hours, poured into 150 g of ice-cold water and extracted with benzene. Thus, 31.99 g of the desired compound are obtained, yield 93.4%.

2- (E) -butenedioate (1/1) melts at 128.5-131.5 ° C.

Analysis for C 26 H 38 N 2 O 5 (458.61): Calculated: C% = 68.09, H% = 8.35, HS = 6.10? found: C% »68.28, HS = 8.35, HS = 6.28.

U.V .: * max * 275 nm (t »14196)

Example 4 Preparation of 2 - [(E) - (p-chlorophenylmethylene)] - [- (E) - (3'-diisopropylamino-propoxyimino)] - cyclohexane

Proceed as in Example 3, but starting from 23.57 g (0.1 mol) of 2 - [(E) - (p-chlorophenylmethylene] -cyclohexan-1-one (E) -oxime and 23.55 g (0, 11 moles) of 1-diisopropylamino-3-chloropropane hydrochloride, 35.63 g of the desired compound are obtained, yield 94.5%.

2- (E) -butenedioate (1/1) melts at 87-89.5 ° C.

Analysis for C 26 H 37 ClN 2 O 5 (493.06): calculated: CS * 63.34, HS * 7.56, CIS = 7.19, NS = 5.68; found: C% * 63.30, HS = 7.54, CIS = 7.13, NS = 5.60.

Ö.V .: λ max * 280 nm (L * 17456)

Claims (1)

14 78682 Claim: Process of general formula (I) .CH-CH, XCH, HC (CH 2) 2 I 2 I / q. for the preparation of new therapeutically useful oxime ethers according to cno- (CH 2) 3 -n 2 (i) HC (CH-) 2 CH R and their pharmaceutically acceptable acid addition salts, which oxime ethers have the jossa, Ε configuration, and wherein R represents phenyl or 4-chlorophenyl, characterized in that a) a compound of the general formula (II) CH-CH, C »X (II) II CH R is reacted with the Ε, Ε -configuration of the general formula (III) HC (CH -) - Y - a compound of the formula (CH2) 3-N2 (III) HC (CH3) 2 or an acid addition salt thereof, in which formulas X represents a hydroxyimino group of the formula «N-OH and Y represents a halogen and R represents the same as above, or (b) reacting a compound of general formula (II) having the Ε, Ε configuration with a halogen compound of general formula (IV) Y- (CH2) 3-Hal '(IV) and treating the compound of general formula (V) CH_ f2 I 2 CH0 thus obtained. C = N-O- (CH 2) - Hal '(V) 1 R A compound having the Ε, Ε configuration of the general formula (VI) Hp ( CH, () -NN (VI) HC (CH3) 2 amine or an acid addition salt thereof, wherein Y, X and R are as defined above and Hal 'is halogen, and, if desired, the general formula (I) obtained by method a) or b) is converted ) to a pharmaceutically acceptable acid addition salt thereof or to release a base from the salt. 16 78682 For the treatment of a therapeutically active oximeter with Ε, Ε-configuration and uptake of all formulas (I) .CH, / H. dL XCH, HC (CH) I 2 I 2/3 CH, C = N-0 - (CH) -N (I) / 2 3 \ XC HC (CH) y 3 2 CH R color R star for phenyl or 4-chlorophenylr as well as pharmaceutical lamps configuration and use of all formulas (II) CH »f * f» CH »C = X (II) II CH R is the same as for the formation of all formulas (III) HC (CH»), / 3 2 Y- (CH2 ) 3-N 2 - (III) HC (CH 3) 2 or, in the case of a hydrogenation moiety, i represents a form X represented by a hydroxyimino group in the form = = N-OH, Y is halogen and R is the same as above, or